Uppgötvun nýrra genaseta í tengslum við áhættu á mergæxli

Introduction: Multiple myeloma (MM) is a plasma cell malignancy originating from bone marrow. Genetics has proven to impact MM susceptibility, with genome-wide association studies (GWAS) discovering 23 genetic loci associated with MM risk. However, MM remains an incurable disease, with much of its heritability unexplained. We hypothesize that SNPs with predicted functional roles have an increased chance of association with MM susceptibility. Specifically, the stringent significance threshold (p<〖5 x 10〗^(-8)) used in GWASs, accounts for the numerous statistical tests performed, increasing the risk of several false negatives. Our approach in reducing the number of tests was prioritizing SNPs with a heightened prior probability of association, according to their likelihood of affecting gene expression or splicing. Materials and methods: This study used discovery GWAS datasets from the InterLymph Consortium and German GWAS, in total accounting for about 4000 cases and 5600 controls. The study included all SNPs with association p-values from 〖5 x 10〗^(-4) to 10^(-7) from the data. Subsequently, SNPs were looked up in relevant GTEx (Genotype-Tissue Expression) tissues, i.e. whole blood and EBV-transformed lymphocytes, determining their function as an expression or splicing quantitative trait loci (eQTL/sQTL). The top candidate SNPs were genotyped for replication in the International Multiple Myeloma rESEarch (IMMEnSE) Consortium including nearly 2000 MM cases and over 1900 controls. Results: In the two discovery datasets, 136 SNPs fit the criteria of association with MM risk including p-values within the chosen threshold and not mapping to known MM risk loci. All SNPs displayed significant meta-analysis results between InterLymph and German GWAS, and only two displayed significant heterogeneity. 38 eQTLs and 3 sQTLs were found in whole blood using GTEx data. After pruning for linkage disequilibrium (LD), and eliminating SNPs with previous genotype results from other studies, one eQTL (rs2664188) was replicated in IMMEnSE. The eQTL was genotyped and meta-analyzed in IMMEnSE, and proved to be significant (OR=1.20, 95%-CI=[1.06;1.36], p=0.0045). Conclusion: A new SNP with significant association with increased MM susceptibility was identified. Further investigation is necessary to determine the effect this eQTL has on MM. This project is included in a larger study, with great potential to identify multiple risks and fill some gaps remaining in MM heritability.Erasmus+ Menntasjóður Læknadeilda